This is the National Phase Application of PCT/GB 00/02232 filed, Jun. 20, 2000.
The present invention relates to a process for the manufacture of morphine-6-glucuronide (M6G) and its analogues and also to new intermediates for their manufacture.
Morphine and its known derivatives are opiates which have pain relief properties and are therefore useful in the treatment of chronic and acute pain encountered in various indications in human and other warm blooded animals. Certain known derivatives may also be used as antidotes in situations of abuse or overdose.
Some Morphine derivatives are described in published patent specifications WO 93/03051, WO 95/16050, and also in patent application PCT/GB 98/01071, the disclosures of which are incorporated herein by way of reference.
In particular, WO 93/03051 describes various substituted morphine-6-glucuronide derivatives, and also various substituted glucuronate ester derivatives useful as intermediates in the manufacture of the morphine-6-glucuronide derivatives.
PCT/GB 98/01071 describes a specific selected range of substituted morphine-6-glucuronide derivatives wherein a C(7)-C(8) linkage of the molecule is di-hydro or otherwise saturated rather than being an ethylenic double bond.
These references also disclose particular advantageous new processes for the preparation of morphine derivatives which avoid the use of heavy metals such as silver and barium described previously by H. Yoshimura et al., Chem. Pharm. Bull., 1968, 16, 2114, and P. A. Carrupt. et al., J. Med. Chem., 1991, 34, 1272 using the Koenigs-Knorr procedure. As described in WO 93/0305, morphine-6-glucuronide can be prepared by conjugating a morphine derivative with a glucuronic acid ester or imidate in the presence of acid catalysis. In the process described in WO 95/16050 the 3-glucuronide moiety in morphine-3,6-glucuronide or substituted morphine-6-glucuronide is subjected to selective enzymatic cleavage using at least one xcex2-glucuronidase. The avoidance of heavy metals permits production of morphine-6-glucuronide and its derivatives devoid of heavy metals which allows the products to be made available for pharmaceutical use.
An object of the present invention is to provide a process, which can employ cheaper reagents and reactants in equimolar amounts, for making M6G and dihydro M6G and related compounds of the following general formula, in which R1, R2 and R3 are defined below: 
R1=alkyl both branched and un-branched, aryl, silyl or acyl
R2=glycoside ester
R3=alkyl, aryl, hydrogen or (CH2)nX where n is an integer and X=NRR4 where R and R4 are hydrogen, alkyl, aryl or acyl.
The C(7)-C(8) linkage may be olefin or dihydro or olefin adducts CHX-CHY (X,Y=epoxy, halogen, hydrohalogen).
The present invention is based on the use of new intermediates which have been prepared, namely 1-iodo derivatives of glucuronate esters. Glycosyl iodides previously have been regarded as unstable and unsuitable as intermediates in synthesis (R. J. Ferrier in Carbohydrate Chemistry, ed. J. F. Kennedy, OUP, 1984, 448. P. M. Collins and R. J. Ferrier, Monosaccharides, Wiley, 1995, 163).
The method of the invention consists of the conjugation of an optionally substituted 1-haloglucuronate ester, preferably the 1-iodo derivative, with morphine or substituted morphine, using iodine or an iodonium reagent. This may be followed by a conversion of R1 in Formula 1 into hydrogen and as appropriate the removal of the ester groups from the glucuronic residue at R2 (Formula 1).
Preferred substituents R1, R2 and R3 of the optionally substituted product M6G are given in the following table 1. The preferred substituents R1, R2 and R3 for the morphine component used in the process are:
R1=H; acyl, especially acetyl, benzoyl, isobutyryl or pivaloyl; trialkylsilyl, especially t-butyldimethylsilyl; lower alkyl, especially methyl; and methyl
xcex2-D-(2,3,4-tri-O-acyl) glucuronate
R2=H
R3=methyl, methyl N-oxide (NMe) or (CH2)nX where
X=NRR4, R and R4 being H, alkyl, aryl or acyl; OR or halogen, and the C(7)-C(8) linkage may be olefin, dihydro or olefin adducts CHX-CHY (X,Y=epoxy, halogen, hydrohalogen).
The 1-haloglucuronate ester and substituted versions thereof as used in the process of the invention may have the following formula: 
in which:
R1=alkyl or aryl, preferably methyl
R2=acyl, silyl, alkyl, benzyl or aryl, preferably acetyl, isobutyryl or pivaloyl and X=halogen in the xcex1 or xcex2 configuration, preferably Br or I, more preferably I.
Specific examples (which are not limiting) of the preparations of these compounds are given below. In a preferred embodiment of the present invention the phenolic group of the M6G or substituted M6G is protected. The protected esters may then be isolated followed by chemical or enzymic hydrolysis or cleavage to liberate the free M6G or substituted M6G,
Preparations of the compounds of the type shown in Formula 2 in which X=O-acyl are well known in the literature (G. N. Bollenback et al., J. Am. Chem. Soc., 1955, 77, 3310; J. Vlahov and G. Snatzke, Liebigs Ann. Chem., 1983, 570; WO 93/03051).
A tetraacyl derivative of this kind may then be converted to the desired 1-halo derivative by treatment with a hydrogen halide (especially HBr), as described in the above references, or more conveniently in the case where X=I is required, by treatment with a Lewis acid and an alkali metal iodide as described for the case R1=Me, R2=MeCO (R. T. Brown et al., J. Chem. Res. (S), 1997, 370) and further exemplified in a non-limiting manner below.
The 1-halosugar derivative may then be condensed with a morphine derivative, in which the phenolic OH group is protected as defined in WO 93/03051, by using elemental iodine or an iodonium derivative such as IBr, ICI or N-iodosuccinimide. This coupling method is very mild and has the advantage that good yields of product are obtained at 1:1 molar ratios of morphine component to carbohydrate; large excesses of carbohydrate are unnecessary, simplifying the workup of the reaction and in particular reducing the need for chromatography. The iodine may be advantageously combined with a promoter or co-catalyst, preferably a Lewis acid, e.g. a Group I, II, III or a transition metal halide such as ZnI2, MgI2, FeCI3 or using ICI or IBr themselves as co-catalysts.
The use of iodine to catalyse glycosidation of alcohols using various bromosugars in the glucose series was reported by R. A. Field et al., Tetrahedron Letters., 1996, 37, 8807. There has however been no realisation of the techniques of the present invention and in particular:
1) the use of iodonium catalysts IBr, ICI and N-iodosuccinimide (NIS) has received little attention (in the case of IBr) and none in the case of ICI or NIS;
2) addition of a glucuronic acid residue is recognised by experts in carbohydrate chemistry as a very demanding process; coupling methods which work with other monosaccarides may be quite ineffective with the corresponding glucuronic acid derivatives (R. R. Schmidt et al., Tetrahedron Lett., 1994, 35, 4763). Indeed, here, iodine itself can be a poor promoter of the coupling of a glucuronic acid derivative of Formula 2 with X=xcex1-Br and the more active promoters may be appropriate in this case;
3) the use of an iodosugar in conjunction with iodine promotion is without precedent.